Non-keratinizing nasopharyngeal carcinoma (NPC) is 100% associated with the presence of the oncogenic human herpesvirus Epstein-Barr virus. It is divided into two sub types: poorly differentiated (type II) and undifferentiated (type III). Type III is by far the most common form of the disease. Although a major world heath problem, NPC remains understudied. Furthermore, because it develops in an occult site and initially presents with symptoms associated with upper respiratory tract infection, it often remains undetected until it has reached an advanced stage. This is critical because early stage disease is readily treatable and potentially curable, whereas therapeutics for advanced stage disease result in high morbidity and relapse rates and there are no effective options for treating metastatic disease. Therefore there is a pressing need for the development of new therapies that target advanced disease. In this study we are using systems biology techniques to identify candidate molecules and processes that contribute to NPC tumor growth and metastasis. The intent is to investigate underlying mechanisms that may also identify targets for new therapies. In this work in vitro and in vivo (mouse) models of NPC tumor growth and metastasis will be developed. In vitro, cultured primary epithelial cells, well characterized NPC cell lines and tumor cells cultured directly from NPC biopsies will be used. In vivo ectopic tumor growth and a newly developed orthotopic NPC metastasis model will be used employing xenotransplanted NPC cell lines and tumor biopsy samples. These models will allow the evaluation of how processes, already identified in preliminary studies, contribute to disease development and progression. These are: 1. to test the idea that type II and type III NPC are distinct at the molecular genetic level based on preferential deregulation of the PI3kinase/Akt/mTOR signaling pathway in type III NPC. Does this deregulation make type III tumors more vulnerable to drugs that target this pathway and will such drugs impede the invasive and metastatic behavior of the tumors in vivo. 2. To study the role of the chemokine CCL5 (RANTES) in mediating epithelial and NPC tumor cell migration, invasion and metastasis. 3. Study the role of the EBV encoded latent proteins LMP1 and LMP2a in tumor growth and metastasis in vivo, activation of the PI3linase/Akt/mTOR signaling pathway and induction of RANTES dependent migration, invasion and metastasis. 4. To develop quantitative profiles of EBV miRNA expression in EBV associated tumors with special emphasis on NPC. Apply clustering algorithms to these data sets to define miRNAs whose expression is up- or down-regulated in NPC in order to identify their target genes and ultimately assess the role of these genes in tumor growth and metastasis in vivo. PUBLIC HEALTH RELEVANCE: Nasopharyngeal carcinoma is an important world health problem especially in people of Southern Chinese origin. Because it is usually diagnosed after progression to an advanced stage, with poor prognosis, there is a pressing need for the development of new therapies that will target the advanced stages of disease. We have taken a multi-faceted approach to understanding the underlying mechanisms regulating NPC tumor growth, invasion and metastasis with the long term goal of developing new candidate therapies that target these processes.